Associated with high morbidity and mortality, lung adenocarcinoma (LUAD) is lacking in effective prognostic prediction and treatment. As chemotherapy drugs commonly used in clinics, microtubule-targeting agents (MTAs) are limited by high toxicity and drug resistance. This research aimed to analyze the expression profile of microtubule-associated genes (MAGs) in LUAD and explore their therapy efficiency and impact on prognosis. Key MAGs were identified as novel molecular targets for targeting microtubules. The LUAD project in The Cancer Genome Atlas (TCGA) database was used to identify differently expressed MAGs. On the one hand, a microtubule-related prognostic signature was constructed and validated, and its links with clinical characteristics and the immune microenvironment were analyzed. On the other hand, hub MAGs were obtained by a protein-protein interaction (PPI) network. Following the expression of hub MAGs, patients with LUAD were classified into two molecular subtypes. A comparison was made of the differences in half-maximal drug inhibitory concentration (IC50) and tumor mutational burden (TMB) between groups. In addition, the influence of MAGs on the anticancer efficacy of different therapies was explored. MAGs, which were included in both the prognosis signature and hub genes, were considered to have great value in prognosis and targeted therapy. They were identified by quantitative real-time polymerase chain reaction (qRT-PCR). A total of 154 differently expressed MAGs were discovered. For one thing, a microtubule-related prognostic signature based on 14 MAGs was created and identified in an external validation cohort. The prognostic signature was used as an independent prognostic factor. For another, 45 hub MAGs were obtained. In accordance with the expression profile of 45 MAGs, patients with LUAD were divided into two subtypes. Distinct differences were observed in TMB and IC50 values of popular chemotherapy and targeted drugs between subtypes. Finally, five genes were included in both the prognosis signature and hub genes, and identified by qRT-PCR. A microtubule-related prognosis signature that can serve as an independent prognostic factor was constructed. Microtubule subtype influenced the efficacy of different treatments and could be used to guide therapy selection. In this research, five key MAGs, including MYB proto-oncogene like 2 (MYBL2), nucleolar and spindle-associated protein 1 (NUSAP1), kinesin family member 4A (KIF4A), KIF15 and KIF20A, were verified and identified. They are promising biomarkers and therapeutic targets in LUAD.
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